Tyrphostin AG1478 Inhibits Encephalomyocarditis Virus and Hepatitis C Virus by Targeting Phosphatidylinositol 4-Kinase IIIα

Cristina M Dorobantu; Christian Harak; Rahel Klein; Lonneke van der Linden; Jeroen R P M Strating; Hilde M van der Schaar; Volker Lohmann; Frank J M van Kuppeveld

doi:10.1128/AAC.01331-16

Tyrphostin AG1478 Inhibits Encephalomyocarditis Virus and Hepatitis C Virus by Targeting Phosphatidylinositol 4-Kinase IIIα

Antimicrob Agents Chemother. 2016 Sep 23;60(10):6402-6. doi: 10.1128/AAC.01331-16. Print 2016 Oct.

Authors

Cristina M Dorobantu¹, Christian Harak², Rahel Klein², Lonneke van der Linden³, Jeroen R P M Strating¹, Hilde M van der Schaar¹, Volker Lohmann², Frank J M van Kuppeveld⁴

Affiliations

¹ Department of Infectious Diseases & Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
² Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany.
³ Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
⁴ Department of Infectious Diseases & Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands [email protected].

Abstract

Encephalomyocarditis virus (EMCV), like hepatitis C virus (HCV), requires phosphatidylinositol 4-kinase IIIα (PI4KA) for genome replication. Here, we demonstrate that tyrphostin AG1478, a known epidermal growth factor receptor (EGFR) inhibitor, also inhibits PI4KA activity, both in vitro and in cells. AG1478 impaired replication of EMCV and HCV but not that of an EMCV mutant previously shown to escape PI4KA inhibition. This work uncovers novel cellular and antiviral properties of AG1478, a compound previously regarded only as a cancer chemotherapy agent.

MeSH terms

1-Phosphatidylinositol 4-Kinase / antagonists & inhibitors*
1-Phosphatidylinositol 4-Kinase / metabolism
Antiviral Agents / pharmacology*
Dose-Response Relationship, Drug
Encephalomyocarditis virus / drug effects*
Encephalomyocarditis virus / genetics
Encephalomyocarditis virus / physiology
Enzyme Inhibitors / pharmacology*
HeLa Cells / drug effects
HeLa Cells / virology
Hepacivirus / drug effects*
Hepacivirus / physiology
Humans
Molecular Targeted Therapy / methods
Mutation
Quinazolines / pharmacology*
Tyrphostins / pharmacology*
Virus Replication / drug effects

Substances

Antiviral Agents
Enzyme Inhibitors
Quinazolines
Tyrphostins
RTKI cpd
1-Phosphatidylinositol 4-Kinase

Grants and funding

This work was supported by research grants from The Netherlands Organization for Scientific Research (NWO-VENI-863.12.005 to H.M.V.D.S., NWO-VENI-722.012.006 to J.R.P.M.S., NWO-ALW-820.02.018 to F.J.M.V.K., and NWO-VICI-91812628 to F.J.M.V.K.), the European Union 7th Framework (EUVIRNA Marie Curie Initial Training Network, grant agreement number 264286, to F.J.M.V.K.), and grants from the Deutsche Forschungsgemeinschaft (LO 1556/4-1 to V.L.). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.